Aromatic sulfenates for type I phototherapy

ABSTRACT

The present invention discloses novel sulfenate derivatives and their bioconjugates for phototherapy of tumors and other lesions. The sulfenates of the present invention are designed to absorb low-energy ultraviolet, visible, or near-infrared (NIR) region of the electromagnetic spectrum. The phototherapeutic effect is caused by direct interaction of free radicals, the reactive intermediate produced upon photofragmentation of the sulfenate moiety, with the tissue of interest.

FIELD OF THE INVENTION

[0001] This invention relates to novel dye-sulfenate compositions andphototherapeutic procedures using these compositions.

BACKGROUND OF THE INVENTION

[0002] The use of visible and near-infrared (NIR) light in clinicalpractice is growing rapidly. Compounds absorbing or emitting in thevisible or long-wavelength (UV-A, >350 nm) region of the electromagneticspectrum are potentially useful for optical tomographic imaging,endoscopic visualization, and phototherapy. However, a major advantageof biomedical optics lies in its therapeutic potential. Phototherapy hasbeen demonstrated to be a safe and effective procedure for the treatmentof various surface lesions, both external and internal. Its efficacy isakin to radiotherapy, but it advantageously lacks the harmfulradiotoxicity to critical non-target organs.

[0003] Phototherapy has been in existence for many centuries and hasbeen used to treat various skin surface ailments. As early as 1400 B.C.in India, plant extracts (psoralens), in combination with sunlight, wereused to treat vitiligo. In 1903, Von Tappeiner and Jesionek, used eosinas a photosensitizer for treating skin cancer, lupus of the skin, andcondylomata of female genitalia. Over the years, the combination ofpsoralens and ultraviolet A (low-energy) radiation has been used totreat a wide variety of dermatological diseases and manifestationsincluding psoriasis, parapsoriasis, cutaneous T-cell lymphoma, eczema,vitiligo, areata, and neonatal bilirubinemia. Although the potential ofcancer phototherapy has been recognized since the early 1900s,systematic studies to demonstrate safety and efficacy began only in 1967with the treatment of breast carcinoma. In 1975, Dougherty et al.conclusively established that long-term cure is possible withphotodynamic therapy (PDT). Currently, phototherapeutic methods are alsobeing investigated for the treatment of some cardiovascular disorderssuch as atherosclerosis and vascular restenosis, for the treatment ofrheumatoid arthritis, and for the treatment of some inflammatorydiseases such as Chron's disease.

[0004] Phototherapeutic procedures require photosensitizers (i.e.chromophores) having high absorptivity. These compounds shouldpreferably be chemically inert and become activated only uponirradiation with light of an appropriate wavelength. Selective tissueinjury can be induced with light when photosensitizers bind to thetarget tissues, either directly or through attachment to a bioactivecarrier. Furthermore, if the photosensitizer is also a chemotherapeuticagent (e.g., anthracycline antitumor agents), then an enhancedtherapeutic effect can be attained. The key requirements for the designof effective phototherapeutic agents are: (a) large molar extinctioncoefficients, (b) long triplet lifetimes, (c) high yields of singletoxygen and/or other reactive intermediates, viz., free radicals,nitrenes, carbenes, or open-shell ionic species such as carbonium ionsand the like, (d) efficient energy or electron transfer to cellularcomponents, (e) low tendency to form aggregation in an aqueous milieu,(f) efficient and selective targeting of lesions, (g) rapid clearancefrom the blood and non-target tissues, (h) low systemic toxicity, and(i) lack of mutagenicity.

[0005] Photosensitizers operate via two distinct mechanisms, termedTypes 1 and 2. The type 1 mechanism is shown in the following scheme:

hv SENSITIZER_(→)(SENSITIZER)*(SENSITIZER)* +TISSUE_(→)TISSUE DAMAGE

[0006] Type 1 mechanisms involve direct energy or electron transfer fromthe photosensitizer to the cellular components thereby causing celldeath. Type 2 mechanisms involve two distinct steps, as shown in thefollowing scheme:

hv SENSITIZER_(→)(SENSITIZER)*(SENSITIZER)*+³O₂(Triplet Oxygen)_(→)¹O₂(Singlet Oxygen)¹O₂(Singlet Oxygen)+TISSUE_(→)TISSUE DAMAGE

[0007] In the first step, singlet oxygen is generated by energy transferfrom the triplet excited state of the photosensitizer to the oxygenmolecules surrounding the tissues. In the second step, collision ofsinglet oxygen with the tissues promotes tissue damage. In both Type 1and Type 2 mechanisms, the photoreaction proceeds via the lowest tripletstate of the sensitizer. Hence, a relatively long triplet lifetime isrequired for effective phototherapy. In contrast, a relatively shorttriplet lifetime is required to avoid photodamage to the tissue causedby photosensitizers.

[0008] The biological basis of tissue injury brought about by tumorphototherapeutic agents has been the subject of intensive study. Variousreasonable biochemical mechanisms for tissue damage have been postulatedeven though the type and number of photosensitizers employed in thesestudies are relatively small. These biochemical mechanisms are asfollows: a) cancer cells upregulate the expression of low densitylipoprotein (LDL) receptors, and photodynamic therapy (PDT) agents bindto LDL and albumin selectively; (b) porphyrin-like substances areselectively taken up by proliferative neovasculature; (c) tumors oftencontain increased number of lipid bodies and are thus able to bind tohydrophobic photosensitizers; (d) a combination of “leaky” tumorvasculature and reduced lymphatic drainage causes porphyrinaccumulation; (e) tumor cells may have increased capabilities forphagocytosis or pinocytosis of porphyrin aggregates; (f) tumorassociated macrophages may be largely responsible for the concentrationof photosensitizers in tumors; and (g) cancer cells may undergoapoptosis induced by photosensitizers. Among these mechanisms, (f) and(g) are the most general and, of these two alternatives, there is ageneral consensus that (f) is the most likely mechanism by which thephototherapeutic effect of porphyrin-like compounds is induced.

[0009] Most of the currently known photosensitizers are commonlyreferred to as photodynamic therapy (PDT) agents and operate via theType 2 mechanism. For example, Photofrin II (a hematoporphyrinderivative) has been recently approved by the United States Food andDrug Administration for the treatment of bladder, esophageal, andlate-stage lung cancers. However, Photofrin II has been shown to haveseveral drawbacks: a low molar absorptivity (ε=3000 M⁻¹), a low singletoxygen quantum yield (φ=0.1), chemical heterogeneity, aggregation, andprolonged cutaneous photosensitivity. Hence, there has been considerableeffort in developing safer and more effective photosensitizers for PDTwhich exhibit improved light absorbance properties, better clearance,and decreased skin photosensitivity compared to Photofrin II. Theseinclude monomeric porphyrin derivatives, corrins, cyanines,phthalocyanines, phenothiazines, rhodamines, hypocrellins, and the like.However, these phototherapeutic agents also mainly operate via the Type2 mechanism.

[0010] Surprisingly, there has not been much attention directed atdeveloping Type 1 phototherapeutic agents, despite the fact that theType 1 mechanism appears to be inherently more efficient than the Type 2mechanism. First, unlike Type 2, Type 1 photosensitizers do not requireoxygen for causing cellular injury. Second, the Type 1 mechanisminvolves two steps (photoexcitation and direct energy transfer), whereasthe Type 2 mechanism involves three steps (photoexcitation, singletoxygen generation, and energy transfer). Furthermore, certain tumorshave hypoxic regions, which renders the Type 2 mechanism ineffective.However, in spite of the drawbacks associated with the Type 2 mechanism,only a small number of compounds have been developed that operatethrough the Type 1 mechanism, e.g. anthracyline antitumor agents.

[0011] Thus, there is a need to develop effective phototherapeuticagents that operate via the Type 1 mechanism. Phototherapeutic efficacycan be further enhanced if the excited state photosensitizers cangenerate reactive intermediates such as free radicals, nitrenes,carbenes, and the like, which have much longer lifetimes than theexcited chromophore and have been shown to cause considerable cellinjury.

SUMMARY OF THE INVENTION

[0012] The present invention discloses novel aromatic sulfenates thatreact mainly by a type 1 mechanism for phototherapy of tumors and otherlesions. More specifically, the present invention discloses sulfenateshaving the formula,

[0013] wherein E is selected from the group consisting of somatostatin,heat sensitive bacterioendotoxin, neurotensin, bombesin,cholecystekinin, steroid, and carbohydrate receptor binding molecules,and dihydroxyindolecarboxylic acid. X is selected from the groupconsisting of —(R⁵)NOC—, —(R⁵)NOCCH₂O—, —(R⁵)NOCCH₂CH₂O—, and—HNC(═S)NH. R¹ to R⁵ are independently selected from the groupconsisting of hydrogen, C1-C10 alkyl, C5-C10 aryl, C1-C10polyhydroxyalkyl and C1-C10 polyalkoxyalkyl. Q is either a single bondor an alkenyl, aromatic, or heteroaromatic radical derived from acompound selected from the group consisting of olefins, benzenes,naphthalenes, naphthoquinones, fluorines, anthracenes, anthraquinones,phenanthrenes, tetracenes, naphthacenediones, pyridines, quinolines,isoquinolines, indoles, isoindoles, pyrroles, imidiazoles, oxazoles,thiazoles, pyrazoles, pyrazines, purines, benzimidazoles, furans,benzofurans, dibenzofurans, carbazoles, acridines, acridones,phenanthridines, thiophenes, benzothiophenes, dibenzothiophenes,xanthenes, xanthones, flavones, coumarins, and anthacylines; and Ar isan aromatic or heteroaromatic radical derived from a compound selectedfrom the group consisting of benzenes, naphthalenes, naphthoquinones,diphenylmethanes, fluorenes, anthracenes, anthraquinones, phenanthrenes,tetracenes, naphthacenediones, pyridines, quinolines, isoquinolines,indoles, isoindoles, pyrroles, imidiazoles, oxazoles, thiazoles,pyrazoles, pyrazines, purines, benzimidazoles, furans, benzofurans,dibenzofurans, carbazoles, acridines, acridones, phenanthridines,thiophenes, benzothiophenes, dibenzothiophenes, xanthenes, xanthones,flavones, coumarins, and anthacylines.

[0014] The present invention also discloses a method of performing atherapeutic procedure using the sulfenate compounds of the presentinvention. An effective amount of a sulfenate photosensitizer having theformula,

[0015] is administered to a subject. E is selected from the groupconsisting of somatostatin, heat sensitive bacterioendotoxin,neurotensin, bombesin, cholesystekinin, steroid, and carbohydratereceptor binding molecules, and dihydroxyindolecarboxylic acid. X isselected from the group consisting of —(R⁵)NOC—, —(R⁵)NOCCH₂O—,—(R⁵)NOCCH₂CH₂O—, and —HNC(═S)NH, R¹ to R⁵ are independently selectedfrom the group consisting of hydrogen, C1-C10 alkyl, C5-C10 aryl, C1-C10polyhydroxyalkyl, and C1-C10 polyalkoxyalkyl. Q is either a single bondor an alkenyl, aromatic, or heteroaromatic radical derived from acompound selected from the group consisting of olefins, benzenes,naphthalenes, naphthoquinones, fluorenes, anthracenes, anthraquinones,phenanthrenes, tetracenes, naphthacenediones, pyridines, quinolines,isoquinolines, indoles, isoindoles, pyrroles, imidiazoles, oxazoles,thiazoles, pyrazoles, pyrazines, purines, benzimidazoles, furans,benzofurans, dibenzofurans, carbazoles, acridines, acridones,phenanthridines, thiophenes, benzothiophenes, dibenzothiophenes,xanthenes, xanthones, flavones, coumarins, and anthacylines; Ar is anaromatic or heteroaromatic radical derived a compound selected from thegroup consisting of benzenes, naphthalenes, naphthoquinones,diphenylmethanes, fluorenes, anthracenes, anthraquinones, phenanthrenes,tetracenes, naphthacenediones, pyridines, quinolines, isoquinolines,indoles, isoindoles, pyrroles, imidiazoles, oxazoles, thiazoles,pyrazoles, pyrazines, purines, benzimidazoles, furans, benzofurans,dibenzofurans, carbazoles, acridines, acridones, phenanthridines,thiophenes, benzothiophenes, dibenzothiophenes, xanthenes, xanthones,flavones, coumarins, and anthacylines. The photosensitizer is allowed toaccumulate in target tissue which is exposed to light of wavelengthbetween 300 and 950 nm with sufficient power and fluence rate to performthe phototherapeutic procedure. The photoexcitation of the aromaticchromophore effects rapid intramolecular energy transfer to thesulfenate group, resulting in bond rupture and the production of tworeactive free radicals which cause cellular injury.

[0016] These and other advantages and embodiments of the inventivecompounds and methods will be apparent in view of the following figures,description, and examples.

BRIEF DESCRIPTION OF THE DRAWINGS

[0017]FIG. 1 is a schematic mechanism for activation of the inventivecompounds;

[0018]FIG. 2 is a schematic mechanism for the synthesis of a diol inaccordance with the present invention;

[0019]FIG. 3 is a schematic mechanism for the synthesis of an acridonederivative;

[0020]FIG. 4 is a schematic mechanism for the synthesis of an acridinesulfenate derivative;

[0021]FIG. 5 is a schematic mechanism for the synthesis of ananthraquinone-sulfate derivative;

[0022]FIG. 6 is a schematic mechanism for the synthesis of a xanthenederivative;

[0023]FIG. 7 is a schematic mechanism for the synthesis of asteroid-photosensitizer conjugate derivative;

[0024]FIG. 8 is a schematic mechanism for delivering a photosensitizerto the site of a lesion by attaching it to a biosynthetic intermediate.

DETAILED DESCRIPTION OF THE INVENTION

[0025] The present invention discloses novel sulfenate derivatives andtheir bioconjugates for phototherapy of tumors and other lesions.

[0026] The compounds have the general formula,

[0027] wherein E is either a hydrogen atom or is selected from the groupconsisting of antibodies, peptides, peptidomimetics, carbohydrates,glycomimetics, drugs, hormones, or nucleic acids; X is selected from thegroup consisting of —(R⁵)NOC—, —(R⁵)NOC—, —(R⁵)NOCCH₂CH₂O—,—(R⁵)NOCCH₂CH₂O—, —OCN(R⁵)—, —HNC(═S)NH—, and HNC(═O)NH—; Q is either asingle bond or an alkenyl, aromatic, or heteroaromatic radical derivedfrom a compound selected from the group consisting of olefins, benzenes,naphthalenes, naphthoquinones, fluorenes, anthracenes, anthraquinones,phenanthrenes, tetracenes, naphthacenediones, pyridines, quinolines,isoquinolines, indoles, isoindoles, pyrroles, imidiazoles, oxazoles,thiazoles, pyrazoles, pyrazines, purines, benzimidazoles, furans,benzofurans, dibenzofurans, carbazoles, acridines, acridones,phenanthridines, thiophenes, benzothiophenes, dibenzothiophenes,xanthenes, xanthones, flavones, coumarins, and anthacylines; R¹ to R⁵are independently selected from the group consisting of hydrogen, C1-C10alkyl, C5-C10 aryl, C1-C10 polyhydroxyalkyl, and C1-C10 polyalkoxyalkyl;and Ar is an aromatic or heteroaromatic radical derived from a compoundselected from the group consisting of benzenes, naphthalenes,naphthoquinones, diphenylmethanes, fluorenes, anthracenes,anthraquinones, phenanthrenes, tetracenes, naphthacenediones, pyridines,quinolines, isoquinolines, indoles, isoindoles, pyrroles, imidiazoles,oxazoles, thiazoles, pyrazoles, pyrazines, purines, benzimidazoles,furans, benzofurans, dibenzofurans, carbazoles, acridines, acridones,phenanthridines, thiophenes, benzothiophenes, dibenzothiophenes,xanthenes, xanthones, flavones, coumarins, and anthacylines.

[0028] In one embodiment, sulfenates according to the present inventionhave the general formula shown above, wherein E is selected from thegroup consisting of somatostatin, heat sensitive bacterioendotoxin,neurotensin, bombesin, cholesystekinin, steroid, and carbohydratereceptor binding molecules, and dihydroxyindolecarboxylic acid; X isselected from the group consisting of —(R⁵)NOC—, —(R⁵)NOCCH₂O—,—(R⁵)NOCCH₂CH₂O—, and —HNC(═S)NH; Q is a single bond or an olefinic oraromatic radical derived from a compound selected from the groupconsisting of alkenes, benzenes, furans, pyrroles, imidazoles, oxazoles,thiophenes, anthraquinones, quinolines, isoquinolines, indoles,acridines, acridones, phenanthridines, xanthenes, xanthones, andanthacylines; R¹ to R⁵ are independently selected from the groupconsisting of hydrogen, C1-C10 alkyl, C5-C10 aryl, and C1-C10polyhydroxyalkyl; and Ar is an aromatic or heteroaromatic radicalderived from a compound selected from the group consisting of benzenes,diphenylmethanes, fluorenes, anthraquinones, naphthacenediones,pyridines, quinolines, isoquinolines, indoles, acridines, acridones,phenanthridines, xanthenes, xanthones, and anthacylines.

[0029] In an alternative embodiment, sulfenates according to the presentinvention have the general formula shown above, wherein E is selectedfrom the group consisting of somatostatin, heat sensitivebacterioendotoxin (ST), neurotensin, bombesin, cholesystekinin (CCK),steroid, and carbohydrate receptor binding molecules; X is —(R⁵)NOC—,and —(R⁵)NOCCH₂O—; Q is a single bond or is selected from the groupconsisting of benzenes, furans, pyrroles, oxazoles, acridines,acridones, xanthenes, xanthones, and anthracyclines; R¹ to R⁵ areindependently selected from the group consisting of hydrogen, and C1-C10alkyl; and Ar is an aromatic or heteroaromatic radical derived from acompound selected from the group consisting of benzenes,diphenylmethanes, fluorenes, anthraquinones, naphthacenediones,pyridines, quinolines, indoles, acridines, acridones, phenanthridines,xanthenes, xanthones, and anthacyclines.

[0030] These compounds operate mainly by a Type I mechanism as shown inFIG. 1, wherein —O—SR is the sulfenate moiety that produces freeradicals upon photoactivation, and Ar is an aromatic chromophore thatundergoes photosensitization. Aliphatic and aromatic sulfenates can beused for phototherapy, although aromatic sulfenates have better materialhandling properties, as is well known in the art (J. Amaudrut and O.Wiest, The thermal sulfenate-sulfoxide rearrangement: A radical pairmechanism. Journal of the American Chemical Society, 2000, 122,3367-3374, which is expressly incorporated by reference herein in itsentirety). L is a linker between the chromophore and the epitope.Epitope (E) is a particular region of the molecule that is recognizedby, and binds to, the target site on the cell. An epitope is usually,but not always, associated with biomolecules which include hormones,amino acids, peptides, peptidomimetics, proteins, nucleosides,nucleotides, nucleic acids, enzymes, carbohydrates, glycomimetics,lipids, albumins, mono- and polyclonal antibodies, receptors, inclusioncompounds such as cyclodextrins, and receptor binding molecules.Specific examples of biomolecules include steroid hormones for thetreatment of breast and prostate lesions, somatostatin, bombesin, andneurotensin receptor binding molecules for the treatment ofneuroendocrine tumors, cholecystekinin receptor binding molecules forthe treatment of lung cancer; heat sensitive bacterioendotoxin (ST)receptor and carcinoembryonic antigen (CEA) binding molecules for thetreatment of colorectal cancer, dihydroxyindolecarboxylic acid and othermelanin producing biosynthetic intermediates for melanoma, integrinreceptor and atheroscleratic plaque binding molecules for the treatmentof vascular diseases, and amyloid plaque binding molecules for thetreatment of brain lesions. Biomolecules for use in the presentinvention may also include synthetic polymers. Examples of syntheticpolymers include polyaminoacids, polyols, polyamines, polyacids,oligonucleotides, aborols, dendrimers, and aptamers. Coupling ofdiagnostic and radiotherapeutic agents to biomolecules can beaccomplished by methods well known in the art as disclosed in Hnatowichet al., Radioactive Labeling of Antibody. A simple and efficient method.Science, 1983, 220, 613-615; A. Pelegrin et al., Photoimmunodiagnosiswith antibody-fluorescein conjugates: in vitro and in vivo preclinicalstudies. Journal of Cellular Pharmacology, 1992, 3,141-145; and U.S.Pat. No. 5,714,342, each of which are expressly incorporated byreference herein in their entirety. Successful specific targeting offluorescent dyes to tumors using antibodies and peptides for diagnosticimaging of tumors has been demonstrated by us and others, for example,S. A. Achilefu et al., Novel receptor-targeted fluorescent contrastagents for in vivo tumor imaging, Investigative Radiology, 2000, 35(8),479-485; B. Ballou et al., Tumor labeling in vivo usingcyanine-conjugated monoclonal antibodies, Cancer Immunology andImmunotherapy, 1995, 41, 247-263; K. Licha et al., New contrast agentfor optical imaging: acid-cleavable conjugates of cyanine dyes withbiomolecules, In Biomedical Imaging: Reporters, Dyes, andInstrumentation, D. J. Bornhop, C. Contag, and E. M. Sevick-Muraca(Eds.), Proceedings of SPIE, 1999, 3600, 29-35, each of which areexpressly incorporated by reference herein in their entirety. Therefore,the inventive receptor-targeted phototherapeutic agents are expected tobe effective in the treatment of various lesions.

[0031] In the process outlined in FIG. 1, the photoexcitation of thearomatic chromophore effects rapid intramolecular energy transfer to thesulfenate group, resulting in bond rupture and production of tworeactive free radicals which cause cellular injury.

[0032] For targeting purposes, external attachment of an epitope isused. If the aromatic sulfenate compounds themselves preferentiallyaccumulate in the target tissue, however, an additional binding groupmay not be needed. For example, if Ar is an anthracycline moiety, itwill bind to cancer cells directly and would not require an epitope fortargeting purposes.

[0033] The synthesis of sulfenate derivatives is accomplished by themethod disclosed in D. L. Pasto and F. Cottard, Demonstration of thesynthetic utility of the generation of alkoxy radicals by thephoto-induced, homolytic dissociation of alkyl 4-nitrobenzenesulfenates,Tetrahedron Letters, 1994, 35(25), 4303-4306, which is expresslyincorporated by reference herein in its entirety. This method generallyinvolves the condensation of sulfenyl chlorides with alcohols in thepresence of an organic base. The sulfenate derivatives of the presentinvention contain additional functionalities that can be used to attachvarious types of biomolecules, synthetic polymers, and organizedaggregates for selective delivery to various organs or tissues ofinterest.

[0034] A diol 1 is prepared by the reaction of methyl magnesium bromidewith methyl 4-hydroxybenzoate. Referring to FIG. 2, alkylation of theresulting phenol with methyl bromoacetate, condensation of the tertiaryalcohol with 4-nitrobenzenesulfenyl chloride, and saponification of theester affords an intermediate acid 2. This acid 2 is then converted tothe corresponding active ester using N-hydroxysuccimide (NHS) anddicyclohexylcarbodiimide (DCC). The active ester can be attached to anydesired biomolecule of interest to form an aromatic sulfenate 3.Alternatively, the acid 2 can also be directly condensed with anybiomolecule using automated peptide synthesizer. Specifically, thebiomolecule of the present invention pertains to those binding tocolorectal, cervical, ovarian, lung, and neuroendocrine tumors. Theseinclude somatostatin, cholesystekinin, bombesin, neuroendrocrine, and STreceptor binding compounds.

[0035] An acridone derivative is prepared according to FIG. 3. Thestarting material 4 is prepared according to a standard method known toone of skill in the art, as disclosed in K. Matsumura,1-Aminoacridine-4-carboxylic acid., Journal of the American ChemicalSociety, 1938, 32, 591-592, which is expressly incorporated by referenceherein in its entirety. An aminoacridone 4 is converted to a phenol by astandard method of diazotization of the amino group followed bydisplacement of the diazonium group with sodium hydroxide. The phenol 5is converted to the corresponding p-nitrobenzenesulfenate and thenconjugated to the biomolecules directly using an automated peptidesynthesizer, or indirectly by the active ester route, to form theinventive acridine derivative 6.

[0036] A typical preparation of acridine-sulfenate derivative isoutlined in FIG. 4. A thiol 7 is prepared from the known startingmaterial 9-chloroacridone. It is converted to the corresponding sulfenylchloride, condensed with methyl 3-hydroxy-3-methylbutyrate, andsaponified to acid 8. The sulfenate-acid can be condensed with thedesired biomolecules by the process previously described.

[0037] The anthraquinone-sulfenate derivatives can be synthesizedaccording to FIG. 5. A diacid chloride 10 is reacted with a lactone 11under Friedel-Crafts conditions followed by saponification to thecorresponding hydroxyanthraquinone 12. It is then condensed withp-nitrobenzenesulfenyl chloride and conjugated to the desiredbiomolecule directly to form an inventive derivative 14. Alternatively,the lactone 10 could be hydrolyzed to the acid and then coupled to thebiomolecule by conventional methods.

[0038] The xanthene derivative can be prepared according to FIG. 6. Axanthone benzyl ether 15 is prepared from the known 4-hydroxyxanthone byalkylation with benzylbromide. The compound 15 was converted to theether 16 in three steps: bromination, Grignard reaction withethylformate, and Grignard reaction with methylmagnesium bromide.Deprotection of the t-butyl group with HCl followed by alkylation withmethyl bromoacetate provides a tertiary alcohol 17. The tertiary alcohol17 is then condensed with p-nitrobenzenesulfenyl chloride, saponified,and conjugated to the desired biomolecules mentioned previously.

[0039] The novel compositions of the present invention may vary widelydepending on the contemplated application. For tumors, the biomoleculeis selected from the class of tumor markers including, but not limitedto, somatostatin, bombesin, neurotensin, cholesystekinin, heat sensitivebacterioendotoxin, estrogen, and progesterone receptor bindingcompounds. For vascular lesions, the biomolecule may be selected fromthe class of integrins, selecting, vascular endothelial growth factor,fibrins, tissue plasminogen activator, thrombin, LDL, HDL, SialylLewis^(X) and its mimics, and atherosclerotic plaque binding compounds.A typical synthetic scheme of a steroid-photosensitizer conjugate isshown in FIG. 7. Estrone is protected as the t-butyl ether 19 andreduced with sodium borohydride to a mono protected estradiol 20, whichis then condensed with p-nitrobenzenesulfenyl chloride. Deprotection ofthe t-butyl group yields the steroid-photosensitizer conjugate 21.

[0040] As previously described, some compounds accumulate in tumors orother lesions without the assistance of a bioactive carrier.Administration of δ-aminolevulinic acid, an intermediate in porphyrinbiosynthesis, results in a two-fold uptake of porphyrins in tumorscompared to normal tissues. Similarly, administration ofdihydroxyindole-2-carboxylic acid, an intermediate in melaninbiosynthesis, produces substantially enhanced levels of melanin inmelanoma cells compared to normal cells. Thus, a photosensitizer may bedelivered to the site of lesion by attaching it to a biosyntheticintermediate, as shown in FIG. 8. The mono sulfenate 23 is prepared bythe reaction of p-nitrobenzenesulfenyl chloride 22 with ethylene glycoland is condensed with an indole derivative 24. Hydrolysis of thediacetate provides the conjugate 25.

[0041] Methods of performing therapeutic procedures with the inventivecompounds are also disclosed. An effective amount of the inventivecompounds in a pharmaceutically acceptable formulation is administeredto a patient. For example, parenteral administration advantageouslycontains a sterile aqueous solution or suspension of the photosensitizerin a concentration ranging from about 1 nM to about 0.5 M. Preferredparenteral formulations have a concentration of 1 μM to 10 mM. Suchsolutions also may contain pharmaceutically acceptable buffers,emulsifiers, surfactants, and, optionally, electrolytes such as sodiumchloride. Formulations for enteral administration may vary widely, as iswell known in the art. In general, such formulations are liquids, whichinclude an effective amount of the complexes in aqueous solution orsuspension. Such enteral compositions may optionally include buffers,surfactants, emulsifiers, thixotropic agents, and the like. Compoundsfor oral administration may also contain flavoring agents and otheringredients for enhancing their organoleptic qualities. Formulations fortopical delivery may also contain liquid or semisolid excipients toassist in the penetration of the photosensitizer. The compounds may alsobe delivered in an aerosol spray. The dose of the photosensitizer mayvary from 0.1 to 500 mg/kg body weight, preferably from 0.5 to 2 mg/kgbody weight. The photosensitizer is allowed to accumulate in the regionof interest, followed by illumination with the light of wavelength 300to 1200 nm, preferably 350 to 850 nm, at the site of the lesion. If thelesion is on the skin surface, the photosensitizer can be directlyilluminated; otherwise, endoscopic catheters equipped with a lightsource may be employed to achieve phototherapeutic effect. Theintensity, power, duration of illumination, and the wavelength of thelight may vary widely depending on the location and site of the lesions.The wavelength of light may vary from 300 to 1200 nm. The fluence rateis preferably, but not always, kept below 200 mW/cm² to minimize thermaleffects. Appropriate power depends on the size, depth, and the pathologyof the lesion. The novel inventive compounds have broad clinical utilitywhich includes, but is not limited to, phototherapy of tumors,inflammatory processes, and impaired vasculature.

[0042] The inventive compounds can be formulated into diagnostic ortherapeutic compositions for enteral, parenteral, topical, or cutaneousadministration. Topical or cutaneous delivery of the photosensitizer mayalso include aerosol formulation, creams, gels, solutions, etc. Thecompounds are administered in doses effective to achieve the desireddiagnostic or therapeutic effect. Such doses may vary widely dependingupon the particular complex employed, the organs or tissues to beexamined, the equipment employed in the clinical procedure, the efficacyof the treatment achieved, and the like. These compositions contain aneffective amount of the phototherapeutic agent along with conventionalpharmaceutical carriers and excipients appropriate for the type ofadministration contemplated. These compositions may also includestabilizing agents and skin penetration enhancing agents.

[0043] The following example illustrates a specific embodiment of theinvention pertaining to the preparation and properties of a typicalbioconjugate derived from bombesin, a bioactive peptide, and aphototherapeutic molecule, sulfenate.

EXAMPLE Synthesis of Sulfentate-bombesin (7-14) Conjugate

[0044] The peptide is prepared by fluorenylmethoxycarbonyl (Fmoc) solidphase peptide synthesis strategy with a commercial peptide synthesizerfrom Applied Biosystems (Model 432A SYNERGY Peptide Synthesizer). Thefirst peptide cartridge contains Wang resin pre-loaded with an amideresin on 25 -μmole scale. The amino acid cartridges are placed on thepeptide synthesizer and the product is synthesized from the C- to theN-terminal position. Coupling of the Fmoc-protected amino acids (75μmol) to the resin-bound free terminal amine (25 μmol) is carried outwith 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate (HBTU, 75 μmol)/N-hydroxybenzotriazole (HOBt, 75μmol). Each Fmoc protecting group on the solid support was removed with20% piperidine in dimethylformamide before the subsequent amino acid wascoupled to it. The last cartridge contains sulfenate acid, which iscoupled to the peptide automatically, thus avoiding the need forpost-synthetic manipulations.

[0045] After the synthesis is completed, the product is cleaved from thesolid support with a cleavage mixture containing trifluoroacetic acid(85%):water (5%):phenol (5%):thioanisole (5%) for 6 hours. Thepeptide-sulfenate conjugate is precipitated with t-butyl methyl etherand lyophilized in water:acetonitrile (2:3) mixture. The conjugate ispurified by HPLC and analyzed with LC/MS. The sulfenate-bombesin (7-14)conjugate has the following molecular structure:p-azidotetrafluorobenzoyl-Gln-Trp-Ala-Val-Gly-His-Leu-Met-NH₂.

[0046] As would be apparent to skilled artisans, various changes andmodifications are possible and are contemplated within the scope of theinvention described. It should be understood that the embodiments of thepresent invention shown and described in the specification are onlyspecific embodiments of the inventors who are skilled in the art and arenot limiting in any way. Therefore, various changes, modifications oralterations to those embodiments may be made or resorted to withoutdeparting from the spirit of the invention and the scope of thefollowing claims. The references cited are expressly incorporated byreference. For example, although the compositions of the presentinvention are primarily directed at therapy, most of the compoundscontaining polycyclic aromatic chromophores can also be used for opticaldiagnostic imaging purposes.

1 1 1 8 PRT Artificial Sequence The sulfenate-bombesin (7-14) conjugatehas the following molecular structurep-azidotetrafluorobenzoyl-Gln-Trp-Ala-Val-Gly-His-Leu-Met-NH2. 1 Gln TrpAla Val Gly His Leu Met 1 5

What is claimed is:
 1. A sulfenate compound having the formula

wherein E is selected from the group consisting of somatostatin receptorbinding molecules, heat sensitive bacterioendotoxin receptor bindingmolecules, neurotensin receptor binding molecules, bombesin receptorbinding molecules, cholesystekinin receptor binding molecules, steroidreceptor binding molecules, and carbohydrate receptor binding molecules,and dihydroxyindolecarboxylic acid; X is selected from the groupconsisting of —(R⁵)NOC—, —(R⁵)NOCCH₂O—, —(R⁵)NOCCH₂CH₂O—, and—HNC(═S)NH; R¹ to R⁵ are independently selected from the groupconsisting of hydrogen, C1-C10 alkyl, C5-C10 aryl, C1-C10polyhydroxyalkyl, and C1-C10 polyalkoxyalkyl; Q is either a single bondor an alkenyl, aromatic, or heteroaromatic radical derived from acompound selected from the group consisting of olefins, benzenes,naphthalenes, naphthoquinones, fluorenes, anthracenes, anthraquinones,phenanthrenes, tetracenes, naphthacenediones, pyridines, quinolines,isoquinolines, indoles, isoindoles, pyrroles, imidiazoles, oxazoles,thiazoles, pyrazoles, pyrazines, purines, benzimidazoles, furans,benzofurans, dibenzofurans, carbazoles, acridines, acridones,phenanthridines, thiophenes, benzothiophenes, dibenzothiophenes,xanthenes, xanthones, flavones, coumarins, and anthacylines; and Ar isan aromatic or heteroaromatic radical derived from a compound selectedfrom the group consisting of benzenes, naphthalenes, naphthoquinones,diphenylmethanes, fluorenes, anthracenes, anthraquinones, phenanthrenes,tetracenes, naphthacenediones, pyridines, quinolines, isoquinolines,indoles, isoindoles, pyrroles, imidiazoles, oxazoles, thiazoles,pyrazoles, pyrazines, purines, benzimidazoles, furans, benzofurans,dibenzofurans, carbazoles, acridines, acridones, phenanthridines,thiophenes, benzothiophenes, dibenzothiophenes, xanthenes, xanthones,flavones, coumarins, and anthacylines.
 2. The compound of claim 1wherein E is selected from the group consisting of somatostatin receptorbinding molecules, heat sensitive bactenioendotoxin receptor bindingmolecules, neurotensin receptor binding molecules, bombesin receptorbinding molecules, cholesystekinin receptor binding molecules, andsteroid receptor binding molecules; X is selected from the groupconsisting of —(R⁵)NOC—, and —(R⁵)NOCCH₂O—; Q is a single bond; R¹ to R⁵are independently selected from the group consisting of hydrogen, C1-C10alkyl, C5-C10 aryl, and C1-C10 polyhydroxyalkyl; and Ar is an aromaticradical derived from benzene.
 3. The compound of claim 1 wherein E isselected from the group consisting of somatostatin receptor bindingmolecules, heat sensitive bactenioendotoxin receptor binding molecules,neurotensin receptor binding molecules, bombesin receptor bindingmolecules, cholesystekinin receptor binding molecules, and steroidreceptor binding molecules; X is selected from the group consisting of—(R⁵)NOC—, and —(R⁵)NOCCH₂O—; Q is an alkenyl radical derived fromolefins; R¹ to R⁵ are independently selected from the group consistingof hydrogen, C1-C10 alkyl, C5-C10 aryl, and C1-C10 polyhydroxyalkyl; andAr is an aromatic radical derived from benzene.
 4. The compound of claim1 wherein E is selected from the group consisting of somatostatinreceptor binding molecules, heat sensitive bacterioendotoxin receptorbinding molecules, neurotensin receptor binding molecules, bombesinreceptor binding molecules, cholesystekinin receptor binding molecules,and steroid receptor binding molecules; X is selected from the groupconsisting of —(R⁵)NOC—, and —(R⁵)NOCCH₂O—; Q is an aromatic radicalderived from a compound selected from the group consisting of benzenes,furans, pyrroles, imidazoles, thiophenes, anthraquinones, quinolines,indoles, acridines, acridones, xanthenes, xanthones, phenanthridines,and anthacylines; R¹ to R5 are independently selected from the groupconsisting of hydrogen, C1-C10 alkyl, C5-C10 aryl, and C1-C10polyhydroxyalkyl; and Ar is an aromatic radical derived from benzene. 5.The compound of claim 1 wherein E is selected from the group consistingof somatostatin receptor binding molecules, heat sensitivebacterioendotoxin receptor binding molecules, neurotensin receptorbinding molecules, bombesin receptor binding molecules, cholesystekininreceptor binding molecules, and steroid receptor binding molecules; X isselected from the group consisting of —(R⁵)NOC—, and —(R⁵)NOCCH₂O—; Q isa single bond; R¹ to R⁵ are independently selected from the groupconsisting of hydrogen, C1-C10 alkyl, C5-C10 aryl, and C1-C10polyhydroxyalkyl; and Ar is an aromatic radical derived from anthracene.6. The compound of claim 1 wherein E is selected from the groupconsisting of somatostatin receptor binding molecules, heat sensitivebacterioendotoxin receptor binding molecules, neurotensin receptorbinding molecules, bombesin receptor binding molecules, cholesystekininreceptor binding molecules, and steroid receptor binding molecules; X isselected from the group consisting of —(R⁵)NOC—, and —(R⁵)NOCCH₂O—; Q isan alkenyl radical derived from olefins; R¹ to R⁵ are independentlyselected from the group consisting of hydrogen, C1-C10 alkyl, C5-C10aryl, and C1-C10 polyhydroxyalkyl; and Ar is an aromatic radical derivedfrom anthracene.
 7. The compound of claim 1 wherein E is selected fromthe group consisting of somatostatin receptor binding molecules, heatsensitive bacterioendotoxin receptor binding molecules, neurotensinreceptor binding molecules, bombesin receptor binding molecules,cholesystekinin receptor binding molecules, and steroid receptor bindingmolecules; X is selected from the group consisting of —(R⁵)NOC—, and—(R⁵)NOCCH₂O—; Q is an aromatic radical derived from a compound selectedfrom the group consisting of benzenes, furans, pyrroles, imidazoles,thiophenes, anthraquinones, quinolines, indoles, acridines, acridones,xanthenes, xanthones, phenanthridines, and anthacylines; R¹ to R⁵ areindependently selected from the group consisting of hydrogen, C1-C10alkyl, C5-C10 aryl, and C1-C10 polyhydroxyalkyl; and Ar is an aromaticradical derived from anthracene.
 8. The compound of claim 1 wherein E isselected from the group consisting of somatostatin receptor bindingmolecules, heat sensitive bacterioendotoxin receptor binding molecules,neurotensin receptor binding molecules, bombesin receptor bindingmolecules, cholesystekinin receptor binding molecules, and steroidreceptor binding molecules; X is selected from the group consisting of—(R⁵)NOC—, and —(R⁵)NOCCH₂O—; Q is a single bond; R¹ to R⁵ areindependently selected from the group consisting of hydrogen, C1-C10alkyl, C5-C10 aryl, and C1-C10 polyhydroxyalkyl; and Ar is an aromaticradical derived from acridine.
 9. The compound of claim 1 wherein E isselected from the group consisting of somatostatin receptor bindingmolecules, heat sensitive bactenioendotoxin receptor binding molecules,neurotensin receptor binding molecules, bombesin receptor bindingmolecules, cholesystekinin receptor binding molecules, and steroidreceptor binding molecules; X is selected from the group consisting of—(R⁵)NOC—, and —(R⁵)NOCCH₂O—; Q is an alkenyl radical derived fromolefins; R¹ to R⁵ are independently selected from the group consistingof hydrogen, C1-C10 alkyl, C5-C10 aryl, and C1-C10 polyhydroxyalkyl; andAr is an aromatic radical derived from acridine.
 10. The compound ofclaim 1 wherein E is selected from the group consisting of somatostatinreceptor binding molecules, heat sensitive bacterioendotoxin receptorbinding molecules, neurotensin receptor binding molecules, bombesinreceptor binding molecules, cholesystekinin receptor binding molecules,and steroid receptor binding molecules; X is selected from the groupconsisting of —(R⁵)NOC—, and —(R⁵)NOCCH₂O—; Q is an aromatic radicalderived from a compound selected from the group consisting of benzenes,furans, pyrroles, imidazoles, thiophenes, anthraquinones, quinolines,indoles, acridines, acridones, xanthenes, xanthones, phenanthridines,and anthacylines; R¹ to R⁵ are independently selected from the groupconsisting of hydrogen, C1-C10 alkyl, C5-C10 aryl, and C1-C10polyhydroxyalkyl; and Ar is an aromatic radical derived from acridine.11. The compound of claim 1 wherein E is selected from the groupconsisting of somatostatin receptor binding molecules, heat sensitivebacterioendotoxin receptor binding molecules, neurotensin receptorbinding molecules, bombesin receptor binding molecules, cholesystekininreceptor binding molecules, and steroid receptor binding molecules; X isselected from the group consisting of —(R⁵)NOC—, and —(R⁵)NOCCH₂O—; Q isa single bond; R¹ to R⁵ are independently selected from the groupconsisting of hydrogen, C1-C10 alkyl, C5-C10 aryl, and C1-C10polyhydroxyalkyl; and Ar is an aromatic radical derived fromphenanthridine.
 12. The compound of claim 1 wherein E is selected fromthe group consisting of somatostatin receptor binding molecules, heatsensitive bacterioendotoxin receptor binding molecules, neurotensinreceptor binding molecules, bombesin receptor binding molecules,cholesystekinin receptor binding molecules, and steroid receptor bindingmolecules; X is selected from the group consisting of —(R⁵)NOC—, and—(R⁵)NOCCH₂O—; Q is an alkenyl radical derived from olefins; R¹ to R⁵are independently selected from the group consisting of hydrogen, C1-C10alkyl, C5-C10 aryl, and C1-C10 polyhydroxyalkyl; and Ar is an aromaticradical derived from phenanthridine.
 13. The compound of claim 1 whereinE is selected from the group consisting of somatostatin receptor bindingmolecules, heat sensitive bacterioendotoxin receptor binding molecules,neurotensin receptor binding molecules, bombesin receptor bindingmolecules, cholesystekinin receptor binding molecules, and steroidreceptor binding molecules; X is selected from the group consisting of—(R⁵)NOC—, and —(R⁵)NOCCH₂O —; Q is an aromatic radical derived from acompound selected from the group consisting of benzenes, furans,pyrroles, imidazoles, thiophenes, anthraquinones, quinolines, indoles,acridines, acridones, xanthenes, xanthones, phenanthridines, andanthacylines; R¹ to R⁵ are independently selected from the groupconsisting of hydrogen, C1-C10 alkyl, C5-C10 aryl, and C1-C10polyhydroxyalkyl; and Ar is an aromatic radical derived fromphenanthridine.
 14. The compound of claim 1 wherein E is associated witha biomolecule selected from the group consisting of hormones, aminoacids, peptides, peptidomimetics, proteins, nucleosides, nucleotides,nucleic acids, enzymes, carbohydrates, glycomimetics, lipids, albumins,monoclonal antibodies, polyclonal antibodies, receptors, inclusioncompounds, receptor binding molecules, polyaminoacids, polyols,polyamines, polyacids, oligonucleotides, aborols, dendrimers, andaptamers.
 15. A method of performing a phototherapeutic procedure whichcomprises the steps of: (a) administering to a target tissue in ananimal an effective amount of a sulfenate photosensitizer having theformula

wherein E is selected from the group consisting of somatostatin receptorbinding molecules, heat sensitive bacterioendotoxin receptor bindingmolecules, neurotensin receptor binding molecules, bombesin receptorbinding molecules, cholesystekinin receptor binding molecules, steroidreceptor binding molecules, and carbohydrate receptor binding molecules,and dihyroxyindolecarboxylic acid; X is selected from the groupconsisting of —(R⁵)NOC—, —(R⁵)NOCCH₂O—, —(R⁵)NOCCH₂CH₂O—, and—HNC(═S)NH; R¹ to R⁵ are independently selected from the groupconsisting of hydrogen, C1-C10 alkyl, C5-C10 aryl, C1-C10polyhydroxyalkyl, and C1-C10 polyalkoxyalkyl; Q is either a single bondor an alkenyl, aromatic, or heteroaromatic radical derived from acompound selected from the group consisting of olefins, benzenes,naphthalenes, naphthoquinones, fluorenes, anthracenes, anthraquinones,phenanthrenes, tetracenes, naphthacenediones, pyridines, quinolines,isoquinolines, indoles, isoindoles, pyrroles, imidiazoles, oxazoles,thiazoles, pyrazoles, pyrazines, purines, benzimidazoles, furans,benzofurans, dibenzofurans, carbazoles, acridines, acridones,phenanthridines, thiophenes, benzothiophenes, dibenzothiophenes,xanthenes, xanthones, flavones, coumarins, and anthacylines; and Ar isan aromatic or heteroaromatic radical derived from a compound selectedfrom the group consisting of benzenes, naphthalenes, naphthoquinones,diphenylmethanes, fluorenes, anthracenes, anthraquinones, phenanthrenes,tetracenes, naphthacenediones, pyridines, quinolines, isoquinolines,indoles, isoindoles, pyrroles, imidiazoles, oxazoles, thiazoles,pyrazoles, pyrazines, purines, benzimidazoles, furans, benzofurans,dibenzofurans, carbazoles, acridines, acridones, phenanthridines,thiophenes, benzothiophenes, dibenzothiophenes, xanthenes, xanthones,flavones, coumarins, and anthacylines; and (b) exposing said targettissues with the light of wavelength between 300 and 950 nm withsufficient power and fluence rate to perform the phototherapeuticprocedure.
 16. The method of claim 15 further comprising the step ofallowing said photosensitizer to accumulate in said target tissue. 17.The method of claim 15, wherein E is selected from the group consistingof somatostatin receptor binding molecules, heat sensitivebacterioendotoxin receptor binding molecules, neurotensin receptorbinding molecules, bombesin receptor binding molecules, cholesystekininreceptor binding molecules, and steroid receptor binding molecules; X isselected from the group consisting of —(R⁵)NOC—, and —(R⁵)NOCCH₂O—; Q isa single bond; R¹ to R⁵ are independently selected from the groupconsisting of hydrogen, C1-C10 alkyl, C5-C10 aryl, and C1-C10polyhydroxyalkyl; and Ar is an aromatic radical derived from benzene.18. The method of claim 15, wherein E is selected from the groupconsisting of somatostatin receptor binding molecules, heat sensitivebacterioendotoxin receptor binding molecules, neurotensin receptorbinding molecules, bombesin receptor binding molecules, cholesystekininreceptor binding molecules, and steroid receptor binding molecules; X isselected from the group consisting of —(R⁵)NOC—, and —(R⁵)NOCCH₂O—; Q isan alkenyl radical derived from olefins; R¹ to R⁵ are independentlyselected from the group consisting of hydrogen, C1-C10 alkyl, C5-C10aryl, and C1-C10 polyhydroxyalkyl; and Ar is an aromatic radical derivedfrom benzene.
 19. The method of claim 15, wherein E is selected from thegroup consisting of somatostatin receptor binding molecules, heatsensitive bacterioendotoxin receptor binding molecules, neurotensinreceptor binding molecules, bombesin receptor binding molecules,cholesystekinin receptor binding molecules, and steroid receptor bindingmolecules; X is selected from the group consisting of —(R⁵)NOC—, and—(R⁵)NOCCH₂O—; Q is an aromatic radical derived from a compound selectedfrom the group consisting of benzenes, furans, pyrroles, imidazoles,thiophenes, anthraquinones, quinolines, indoles, acridines, acridones,xanthenes, xanthones, phenanthridines, and anthacylines; R¹ to R⁵ areindependently selected from the group consisting of hydrogen, C1-C10alkyl, C5-C10 aryl, and C1-C10 polyhydroxyalkyl; and Ar is an aromaticradical derived from benzene.
 20. The method of claim 15, wherein E isselected from the group consisting of somatostatin receptor bindingmolecules, heat sensitive bacterioendotoxin receptor binding molecules,neurotensin receptor binding molecules, bombesin receptor bindingmolecules, cholesystekinin receptor binding molecules, and steroidreceptor binding molecules; X is selected from the group consisting of—(R⁵)NOC—, and —(R⁵)NOCCH₂O—; Q is a single bond; R¹ to R⁵ areindependently selected from the group consisting of hydrogen, C1-C10alkyl, C5-C10 aryl, and C1-C10 polyhydroxyalkyl; and Ar is an aromaticradical derived from anthracene.
 21. The method of claim 15, wherein Eis selected from the group consisting of somatostatin receptor bindingmolecules, heat sensitive bacterioendotoxin receptor binding molecules,neurotensin receptor binding molecules, bombesin receptor bindingmolecules, cholesystekinin receptor binding molecules, and steroidreceptor binding molecules; X is selected from the group consisting of—(R⁵)NOC—, and —(R⁵)NOCCH₂O—; Q is an alkenyl radical derived fromolefins; R¹ to R⁵ are independently selected from the group consistingof hydrogen, C1-C10 alkyl, C5-C10 aryl, and C1-C10 polyhydroxyalkyl; andAr is an aromatic radical derived from anthracene.
 22. The method ofclaim 15, wherein E is selected from the group consisting ofsomatostatin receptor binding molecules, heat sensitivebacterioendotoxin receptor binding molecules, neurotensin receptorbinding molecules, bombesin receptor binding molecules, cholesystekininreceptor binding molecules, and steroid receptor binding molecules; X isselected from the group consisting of —(R⁵)NOC—, and —(R⁵)NOCCH₂O—; Q isan aromatic radical derived from a compound selected from the groupconsisting of benzenes, furans, pyrroles, imidazoles, thiophenes,anthraquinones, quinolines, indoles, acridines, acridones, xanthenes,xanthones, phenanthridines, and anthacylines; R¹ to R⁵ are independentlyselected from the group consisting of hydrogen, C1-C10 alkyl, C5-C10aryl, and C1-C10 polyhydroxyalkyl; and Ar is an aromatic radical derivedfrom anthracene.
 23. The method of claim 15, wherein E is selected fromthe group consisting of somatostatin receptor binding molecules, heatsensitive bacterioendotoxin receptor binding molecules, neurotensinreceptor binding molecules, bombesin receptor binding molecules,cholesystekinin receptor binding molecules, and steroid receptor bindingmolecules; X is selected from the group consisting of —(R⁵)NOC—, and—(R⁵)NOCCH₂O—; Q is a single bond; R¹ to R⁵ are independently selectedfrom the group consisting of hydrogen, C1-C10 alkyl, C5-C10 aryl, andC1-C10 polyhydroxyalkyl; and Ar is an aromatic radical derived fromacridine.
 24. The method of claim 15, wherein E is selected from thegroup consisting of somatostatin receptor binding molecules, heatsensitive bacterioendotoxin receptor binding molecules, neurotensinreceptor binding molecules, bombesin receptor binding molecules,cholesystekinin receptor binding molecules, and steroid receptor bindingmolecules; X is selected from the group consisting of —(R⁵)NOC—, and—(R⁵)NOCCH₂O—; Q is an alkenyl radical derived from olefins; R¹ to R⁵are independently selected from the group consisting of hydrogen, C1-C10alkyl, C5-C10 aryl, and C1-C10 polyhydroxyalkyl; and Ar is an aromaticradical derived from acridine.
 25. The method of claim 15, wherein E isselected from the group consisting of somatostatin receptor bindingmolecules, heat sensitive bacterioendotoxin receptor binding molecules,neurotensin receptor binding molecules, bombesin receptor bindingmolecules, cholesystekinin receptor binding molecules, and steroidreceptor binding molecules; X is selected from the group consisting of—(R⁵)NOC—, and —(R⁵)NOCCH₂O—; Q is an aromatic radical derived from acompound selected from the group consisting of benzenes, furans,pyrroles, imidazoles, thiophenes, anthraquinones, quinolines, indoles,acridines, acridones, xanthenes, xanthones, phenanthridines, andanthacylines; R¹ to R⁵ are independently selected from the groupconsisting of hydrogen, C1-C10 alkyl, C5-C10 aryl, and C1-C10polyhydroxyalkyl; and Ar is an aromatic radical derived from acridine.26. The method of claim 15, wherein E is selected from the groupconsisting of somatostatin receptor binding molecules, heat sensitivebacterioendotoxin receptor binding molecules, neurotensin receptorbinding molecules, bombesin receptor binding molecules, cholesystekininreceptor binding molecules, and steroid receptor binding molecules; X isselected from the group consisting of —(R⁵)NOC—, and —(R⁵)NOCCH₂O—; Q isa single bond; R¹ to R⁵ are independently selected from the groupconsisting of hydrogen, C1-C10 alkyl, C5-C10 aryl, and C1-C10polyhydroxyalkyl; and Ar is an aromatic radical derived fromphenanthridine.
 27. The method of claim 15, wherein E is selected fromthe group consisting of somatostatin receptor binding molecules, heatsensitive bacterioendotoxin receptor binding molecules, neurotensinreceptor binding molecules, bombesin receptor binding molecules,cholesystekinin receptor binding molecules, and steroid receptor bindingmolecules; X is selected from the group consisting of —(R⁵)NOC—, and—(R⁵)NOCCH₂O—; Q is an alkenyl radical derived from olefins; R¹ to R⁵are independently selected from the group consisting of hydrogen, C1-C10alkyl, C5-C10 aryl, and C1-C10 polyhydroxyalkyl; and Ar is an aromaticradical derived from phenanthridine.
 28. The method of claim 15, whereinE is selected from the group consisting of somatostatin receptor bindingmolecules, heat sensitive bacterioendotoxin receptor binding molecules,neurotensin receptor binding molecules, bombesin receptor bindingmolecules, cholesystekinin receptor binding molecules, and steroidreceptor binding molecules; X is selected from the group consisting of—(R⁵)NOC—, and —(R⁵)NOCCH₂O—; Q is an aromatic radical derived from acompound selected from the group consisting of benzenes, furans,pyrroles, imidazoles, thiophenes, anthraquinones, quinolines, indoles,acridines, acridones, xanthenes, xanthones, phenanthridines, andanthacylines; R¹ to R⁵ are independently selected from the groupconsisting of hydrogen, C1-C10 alkyl, C5-C10 aryl, and C1-C10polyhydroxyalkyl; and Ar is an aromatic radical derived fromphenanthridine.
 29. The method of claim 15 wherein E is associated witha biomolecule selected from the group consisting of hormones, aminoacids, peptides, peptidomimetics, proteins, nucleosides, nucleotides,nucleic acids, enzymes, carbohydrates, glycomimetics, lipids, albumins,monoclonal antibodies, polyclonal antibodies, receptors, inclusioncompounds, receptor binding molecules, polyaminoacids, polyols,polyamines, polyacids, oligonucleotides, aborols, dendrimers, andaptamers.
 30. The method of claim 29 wherein the effective amount of thesulfenate photosensitizer administered to the target tissue is in arange of about 0.1 mg/kg body weight to about 500 mg/kg body weight. 31.The method of claim 30 wherein the effective amount of the sulfenatephotosensitizer administered to the target tissue is in a range of about0.5 mg/kg body weight to about 2 mg/kg body weight.
 32. The method ofclaim 15 wherein the sulfenate photosensitizer is parenterallyadministered to the target tissue in a formulation including thesulfenate photosensitizer and materials selected from the groupconsisting of pharmaceutically acceptable buffers, emulsifiers,surfactants, and electrolytes.
 33. The method of claim 32 wherein theformulation is parenterally administered to the target tissue in aconcentration in a range of about 1 nM to about 0.5 M.
 34. The method ofclaim 15 wherein the sulfenate photosensitizer is enterally administeredto the target tissue in a formulation including the sulfenatephotosensitizer and materials selected from the group consisting ofbuffers, surfactants, emulsifiers, and thixotropic agents.
 35. Themethod of claim 15 wherein the sulfenate photosensitizer is topicallyadministered to the target tissue in a formulation including thesulfenate photosensitizer and materials selected from the groupconsisting of liquid excipients and semisolid excipients.
 36. The methodof claim 15 wherein the sulfenate photosensitizer is administered in aform selected from the group consisting of an aerosol spray, a cream, agel, and a solution.